Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis

The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer's disease (AD) in today's long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless A & beta;(1-42) monomers into the interstitial fluid, where they seed the formation of toxic amyloid-& beta; oligomers (A & beta;Os) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged A & beta;Os to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating A & beta;Os from ground zero is supported by A & beta;'s own production mediated by target cells' Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, A & beta;Os-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.

Automated summary

The evolution of the human neocortex enabled us to dominate the planet, but there was a glitch in the development of the entorhinal cortical gateway to the hippocampal memory system, leading to Alzheimer's disease (AD). The aging process causes strain and energy costs on the neurons of the lateral entorhinal cortex, resulting in the formation of toxic amyloid-beta oligomers (A & beta;Os) that initiate AD. This study suggests that early treatment with a positively charged peptide or protein that interacts with A & beta;Os, coupled with an inhibitor of CaSR, may be an effective therapeutic combination for AD.